Disorders of the nervous system comprise a wide variety of conditions, and can generally be separated into “neurological disorders” and “psychiatric disorders”. Neurological disorders can be characterized as the product of the death of nervous system cells. Examples of neurological disorders include Parkinson's Disease, which involves the death of dopaminergic neurons, Alzheimer's disease, in which cholinergic neurons are lost, and multiple sclerosis, in which neurons and glia are killed in an autoimmune process. Psychiatric disorders, on the other hand, are the result of dysregulation of neurons, which can result in abnormal levels of various neurochemicals and/or abnormal responsiveness to neurochemicals.
Psychiatric disorders, such as schizophrenia, are major public health concerns. Schizophrenia, for example, affects approximately 2 million Americans. At any particular time, about 20% of the hospital beds in the U.S. are occupied by schizophrenic patients. The illness usually develops between adolescence and age 30 and is characterized by positive symptoms (delusions or hallucinations), negative symptoms (blunted emotions and lack of interest) and disorganized symptoms (confused thinking and speech or disorganized behavior and perception). Additionally, cognitive deficits are also frequently observed, particularly in elderly schizophrenia patients (Purohit et al., 1993, Biol. Psychiatry 33(4):255–260). For some patients, the disorder is lifelong, while others may have periodic episodes of psychosis.
The causes of schizophrenia are essentially unknown. Although it is believed to have a genetic component, environmental factors appear to influence the onset and severity of the disease. Neuropathological changes in schizophrenics may include enlargement of the lateral ventricles, cavities in the brain which are part of the cerebrospinal fluid system. Sometimes, there is a decrease in overall brain mass.
A number of animal models have been developed for schizophrenia, utilizing both non-primate (rat) and primate (monkey) animals. In one commonly used animal model of schizophrenia, phencyclidene (PCP) is chronically administered to the animal subjects, resulting in dysfunctions similar to those seen in schizophrenic humans (Jentsch et al., 1997, Science 277:953–955; Piercey et al., 1988, Life Sci. 43(4):375–385).
Several different theories have been developed regarding the etiology of schizophrenia, including the dopaminergic, glutamatergic, and cholinergic theories of schizophrenia. The dopamine hypothesis posits that positive symptoms result from excess function of the neurotransmitter dopamine in the mesolimbic area of the brain. This hypothesis is based largely on indirect, pharmacological evidence that (1) dopamine-antagonizing drugs are effective antipsychotic agents; (2) dopamine-mimicking drug exacerbate schizophrenic symptoms and (3) certain symptoms of acute paranoid schizophrenia can be elicited in non-schizophrenics by amphetamine, a drug that activates dopamine systems. Conversely, negative symptoms have been associated with regionally localized dopamine deficits in the prefrontal cortex.
The glutamate hypothesis is based, among other things, the actions of phencyclidine (PCP) in the brains of abusers. PCP, which induces a number of symptoms also found in schizophrenia, blocks the N-methyl-D-aspartate (NMDA) receptor, through which glutamate exerts some of its effects. Additionally, observations from the phencyclidine (PCP) animal model of schizophrenia, indicate that glutamate is dramatically increased in the brains of rats chronically dosed with PCP (Moghaddam et al., 1997, J. Neurosci. 17:2921). Inhibition of the rise in glutamate levels with a metabotropic glutamate receptor agonist blocked a variety of schizophrenia symptoms in PCP-dosed rats, including hyperactive behavior, head turning, and memory deficits (Moghaddan et al., 1998, Science 281:1349–1352).
Current treatments for schizophrenia include antipsychotic drugs; electric shock treatment for severe catatonia, depression, or elation; and psychotherapy. Antipsychotic drug treatments generally include both dopamine and acetylcholine antagonists (anticholinergics), although anticholinergics are generally used to treat extrapyramidal side effects (EPS) of commonly used dopamine antagonists, rather than the disorder itself. EPS induced by dopamine antagonists result from dopamine blockade in the striatum and include dyskinesias, especially tardive dyskinesia, which are characterized by uncontrolled movements. In most cases, tardive dyskinesia resolves following discontinuation of dopamine agonist drug therapy, but some patients continue to experience dyskinesia long after termination of dopamine antagonist therapy.
Clopazine, an antipsychotic that affects several receptor systems, is currently viewed as the “gold standard” of drug treatment for schizophrenia. However, although clopazine seems to ameliorate certain symptoms (e.g.; verbal fluency, reaction time and attention), it appears to have an adverse effect on higher level executive functions, such as working memory ability and visual memory. Goldberg et al. (1994) J. Clin. Psychiatry 55:9 (suppl. B). Moreover, many dopamine antagonist antipsychotic drugs are not as effective at controlling the “negative” symptoms, as compared to the “positive” symptoms of schizophrenia (Angrist et al., 1982, Psychopharm. 78:128–130).
U.S. Pat. No. 5,447,948 asserts that dopamine reuptake inhibitors are useful in treating schizophrenic patients suffering from negative symptoms. However, dopamine reuptake inhibitors oppose the effects of clopazine and other dopamine antagonists, potentially nullifying the activity of this group of drugs in the treatment of the positive symptoms of schizophrenia.
U.S. Pat. No. 5,618,531 describes methods of increasing the viability of cells which are administered to the brain or spinal cord of a mammalian subject by attaching the cells to a support matrix. It is indicated that the cells may be used to “neurological disorders,” but not psychiatric disorders. As commonly understood in the art, “neurological disorders” are disorders of the nervous system which involve death or major dysfunction of cells of the nervous system, while “psychiatric disorders” involve the misregulation of cells of the nervous system. For example, Parkinson's disease, which involves the death and dysfunction of dopaminergic neurons, is a neurological disorder, while schizophrenia, which involves the misregulation of neurotransmitter levels, is a psychiatric disorder.
In sum, there remains a need in the art for an effective treatment of the symptoms of schizophrenia, particularly the negative symptoms of schizophrenia and cognitive defects associated with schizophrenia, which will not interfere with treatments for the positive symptoms of the disorder. Additionally, there exists a need in the art for an effective treatment for tardive dyskinesia and other EPS.